Substituted tetracyclic azepine derivatives

ABSTRACT

This invention concerns the compounds of formula (I), the pharmaceutically acceptable salts and stereoisomeric forms thereof, and also the N-oxide forms thereof. ##STR1## wherein: R 1  and R 2  each independently are hydrogen; C 1-6  alkyl; C 1-6  alkylcarbonyl; trihalomethylcarbonyl; C 1-6  alkyl substituted with hydroxy, C 1-6  alkyloxy, carboxyl, C 1-6  alkylcarbonyloxy, C 1-6  alkyloxycarbonyl or aryl; or R 1  and R 2  taken together with the nitrogen atom to which they are attached may form a morpholinyl ring or an optionally substituted heterocycle; R 3 , R 4 , R 5 , R 6 , R 9 , R 10 , R 11  or R 12  each independently are hydrogen, halo, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, amino, mono- or di(C 1-6  alkyl)-amino, C 1-6  alkylcarbonylamino, aminosulfonyl, mono- or di(C 1-6  alkyl)-aminosulfonyl, C 1-6  alkyl, C 1-6  alkyloxy, C 1-6  alkylcarbonyl, C 1-6  alkyloxy-carbonyl; R 7  and R 8  are each independently hydrogen, hydroxy, C 1-6  alkyl, C 1-6  alkyloxy or R 7  and R 8  taken together may form mono- or di(cyano)methylene, or together with the carbon atom to which they are attached form a carbonyl or a spiro substituent; or R 7  and R 8  taken together may form methylene; R 13  is hydrogen, C 1-6  alkyl, or trifluoromethyl; R 14  is hydrogen, C 1-6  alkyl, cyano, or trifluoromethyl; n is zero to 6. These compounds were tested as mCPP-antagonists in rats. The compounds of formula (I) may be used as therapeutic agents in the treatment or the prevention of CNS disorders, cardiovascular disorders or gastrointestinal disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from EP 94.203.178.2, filed on Nov. 2,1994.

This invention concerns substituted tetracyclic azepine derivativeshaving antipsychotic, cardiovascular and gastrokinefic activity andtheir preparations; it further relates to compositions comprising them,as well as their use as a medicine.

Compounds of similar structure are described in U.S. Pat. No. 4,039,558which discloses pyrrolidinodibenzo-azepine, -oxazepine, -thiazepine and-diazepine derivatives, having antihistamine, sedative andantidepressant properties. EP-A-0,421,823 describes similardibenzopyrazino- or benzo-pyrido-pyrazino-azepine derivatives havinganti-allergic and anti-asthmatic activities. The present compoundsdiffer therefrom by the presence of an isoxazolidine ring, and by theirpharmacological properties.

This invention concerns compounds of formula (I) ##STR2## thepharmaceutically acceptable acid or base addition salts and thestereochemically isomeric forms thereof, and also the N-oxide formsthereof, wherein:

R¹ and R² each independently are hydrogen; C₁₋₆ alkyl; C₁₋₆alkylcarbonyl; trihalomethylcarbonyl; C₁₋₆ alkyl substituted withhydroxy, C₁₋₆ alkyloxy, carboxyl, C₁₋₆ alkylcarbonyloxy, C₁₋₆alkyloxycarbonyl or aryl; or R¹ and R² taken together with the nitrogenatom to which they are attached may form a morpholinyl ring or a radicalof formula: ##STR3## wherein: R¹⁵, R¹⁶, R¹⁷ and R¹⁸ each independentlyare hydrogen, halo, trifluoromethyl, or C₁₋₆ alkyl;

m is 1, 2, or 3;

R¹⁹, R²⁰, R²¹ and R²² each independently are hydrogen, or C₁₋₆ alkyl; or

R²¹ and R²² taken together may form a bivalent radical C₄₋₅ alkanediyl;

R²³ is hydrogen; C₁₋₆ alkyl; C₁₋₆ alkylcarbonyl; trihalomethylcarbonyl;

C₁₋₆ alkyloxycarbonyl; aryl; di(aryl)methyl; C₁₋₆ alkyl substituted withhydroxy, C₁₋₆ alkyloxy, carboxyl, C₁₋₆ alkylcarbonyloxy, C₁₋₆alkyloxycarbonyl or aryl;

R³, R⁴, R⁵, R⁶, R⁹, R¹⁰, R¹¹ and R¹² each independently are hydrogen,halo, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, carboxyl,nitro, amino, mono- or di(C₁₋₆ alkyl)amino, C₁₋₆ alkylcarbonylamino,aminosulfonyl, mono- or di(C₁₋₆ alkyl)aminosulfonyl, C₁₋₆ alkyl, C₁₋₆alkyloxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkyloxycarbonyl; R⁷ and R⁸ eachindependently are hydrogen, hydroxy, C₁₋₆ alkyl, C₁₋₆ alkyloxy or R⁷ andR⁸ taken together may form mono- or di(cyano)methylene; a bivalentradical of formula --(CH₂)₂ --, --(CH₂)₃ --, --(CH₂)₄ --, --(CH₂)₅ --,--O--(CH₂)₂ --O--, --O--(CH₂)₃ --O--; or, together with the carbon atomto which they are attached, a carbonyl; or

R⁷ and R⁸ taken together may form methylene;

R¹³ is hydrogen, C₁₋₆ alkyl or trifluoromethyl;

R¹⁴ is hydrogen, C₁₋₆ alkyl, cyano or trifluoromethyl;

n is zero, 1, 2, 3, 4, 5, or 6;

aryl is phenyl; or phenyl substituted with 1, 2 or 3 substituentsselected from halo, hydroxy, C₁₋₆ alkyl and trifluoromethyl.

In the foregoing definitions C₁₋₆ alkyl defines straight and branchchained saturated hydrocarbon radicals having from 1 to 6 carbon atomssuch as, for example, methyl, ethyl, propyl, butyl, 1-methylpropyl,1,1-dimethylethyl, pentyl, hexyl; C₄₋₅ alkanediyl defines bivalentstraight and branch chained saturated hydrocarbon radicals having from 4to 5 carbon atoms such as, for example, 1,4-butanediyl, 1,5-pentanediyl;halo is generic to fluoro, chloro, bromo and iodo. The termmonocyanomethylene stands for a radical of formula ═CHCN, anddicyanomethylene for a radical of formula ═C(CN)₂. In case R⁷ and R⁸taken together form a bivalent radical as defined above, the compoundsof formula (I) are spiro compounds.

The pharmaceutically acceptable acid addition salts as mentionedhereinabove are meant to comprise the therapeutically active non-toxicacid addition salt forms which the compounds of formula (I) are able toform. Said salts can be obtained by treating the base form of thecompounds of formula (I) with appropriate acids such as inorganic acids,for example, hydrohalic acid, e.g. hydrochloric or hydrobromic,sulfuric, nitric, phosphoric and the like acids; or organic acids, suchas, for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic,oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric,methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.

Suitable acids are oxalic acid, in particular (R)- or (S)-malic acid andfumaric acid; especially (S)-malic acid.

The compounds of formula (I) containing acidic protons may also beconverted into their therapeutically active non-toxic metal or amineaddition salt forms by treatment with appropriate organic and inorganicbases. Appropriate base salt forms comprise, for example, the ammoniumsalts, the alkali and earth alkaline metal salts, e.g. the lithium,sodium, potassium, magnesium, calcium salts and the like, salts withorganic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabaminesalts, and salts with amino acids such as, for example, arginine, lysineand the like.

Conversely said salt forms can be converted into the free forms bytreatment with an appropriate base or acid.

The term addition salt as used hereinabove also comprises the solvateswhich the compounds of formula (I) as well as the salts thereof, areable to form. Such solyates are for example hydrates, alcoholates andthe like.

The N-oxide forms of the compounds of formula (I) are meant to comprisethose compounds of formula (I) wherein one or several nitrogen atoms areoxidized to the so-called N-oxide, particularly those N-oxides whereinthe nitrogen bearing the R¹ and R² substituents is N-oxidized.

The term "stereochemically isomeric forms" as used hereinbefore andhereinafter defines all the possible isomeric forms in which thecompounds of formula (I) may occur. Unless otherwise mentioned orindicated, the chemical designation of compounds denotes the mixture ofall possible stereochemically isomeric forms, said mixtures containingall diastereomers and enantiomers of the basic molecular structure.Stereochemically isomeric forms of the compounds of formula (I) andmixtures of such forms are obviously intended to be encompassed byformula (I).

The numbering of the tetracyclic ring-system present in the compounds offormula (I), as defined by Chemical Abstracts nomenclature is shown informula (I'). ##STR4##

The compounds of formula (I) occur as "cis" and "trans" isomers. Saidterms refer to the position of the substituents on the isoxazolidinering and are in accordance with Chemical Abstracts nomenclature. Thenomenclature is unusual in that carbon atom 3b, being part of a cyclicsystem, is not considered as a relevant substituent of carbon atom 3a.When establishing the configuration, the substituent on carbon atom 3a(i.e. "Z") and the substituent with the highest priority on carbon atom2 (i.e. either "X" or "Y") are considered. When "Z" and the substituentwith the highest priority on carbon atom 2 are on the same side of themean plane determined by the isoxazolidine ring then the configurationis designated "cis", if not, the configuration is designated "trans".

The compounds of formula (I) have at least two asymmetric centers,namely carbon atom 3a bearing the substituent R¹³ and carbon atom 2bearing the substituent R¹⁴. Said asymmetric centers and any otherasymmetric center which may be present, are indicated by the descriptorsR and S. When a monocyanomethylene moiety is present in the compounds offormula (I), said moiety may have the E- or Z-configuration.

Of some compounds of formula (I) the absolute stereochemicalconfiguration was not experimentally determined. In those cases thestereochemically isomeric form which was first isolated is designated as"A" and the second as "B", without further reference to the actualstereochemical configuration.

Whenever used hereinafter, the term compounds of formula (I) is meant toalso include the pharmaceutically acceptable acid addition salts, baseaddition salts and all stereoisomeric forms, and also the N-oxide forms.

Particular groups of compounds of formula (I) are those wherein one ormore of the following restrictions apply:

a) R¹ and R² each independently are hydrogen, C₁₋₆ alkyl,trihalomethylcarbonyl, C₁₋₆ alkyl substituted with hydroxy, carboxyl,C₁₋₆ alkylcarbonyloxy; or R¹ and R² taken together with the nitrogenatom to which they are attached form a radical of formula (a) in whichR¹⁵ and R¹⁶ are both hydrogen, a radical of formula (b) in which R¹⁷ andR¹⁸ are both hydrogen, a radical of formula (c) in which R¹⁹ and R²⁰ areboth hydrogen, a radical of formula (d) in which R²¹ and R²² takentogether form a C₄₋₅ alkanediyl radical, or a radical of formula (e) inwhich R²³ is hydrogen, C₁₋₆ alkyl, trihalomethylcarbonyl or aryl;

b) R³, R⁴, R⁵ and R⁶ each independently are hydrogen, halo, C₁₋₆ alkyl,or trifluoromethyl;

c) R⁹, R¹⁰, R¹¹ and R¹² each independently are hydrogen, halo, C₁₋₆alkyl, or trifluoromethyl;

d) R⁷ and R⁸ both are methyl, or in particular hydrogen;

e) R¹³ is methyl, or in particular hydrogen;

f) R¹⁴ is methyl or cyano, or in particular is hydrogen;

g) n is 1, 2, 3 or 4; and particularly is 1;

h) R³, R⁴, R⁵ and R⁶ each independently are C₁₋₆ alkyloxy or money- ordi(C₁₋₆ alkyl)amino;

i) R⁹, R¹⁰, R¹¹ and R¹² each independently are C₁₋₆ alkyloxy or mono- ordi(C₁₋₆ alkyl)amino;

j) R⁷ is methyl and R⁸ is hydrogen; or R⁷ and R⁸ taken together formmethylene.

Of special interest are those compounds of formula (I) or subgroups asdefined above, wherein one of the aromatic substituents R³, R⁴, R⁵, R⁶,R⁹, R¹⁰, R¹¹, R¹² is selected from hydrogen, halo, C₁₋₆ alkyl, ortrifluoromethyl; the remaining aromatic substituents being hydrogen.

Also of special interest are those compounds of formula (I) or subgroupsas defined above, wherein two or more of the aromatic substituents R³,R⁴, R⁵, R⁶, R⁹, R¹⁰, R¹¹, R¹² are selected from fluoro, chloro or bromo;the remaining aromatic substituents being hydrogen.

More interesting are those compounds of special interest wherein thearomatic substituents R⁴, R⁵ and R¹¹ each independently are selectedfrom hydrogen, fluoro, chloro, bromo, methyl or trifluoromethyl; theremaining aromatic substituents being hydrogen.

Preferred compounds are those compounds of formula (I) or subgroups ofcompounds of formula (I) as defined above, wherein R¹ and R² are bothmethyl and n is 1 or 2.

Also preferred are those compounds of formula (I) or subgroups ofcompounds of formula (I) as defined above, wherein R¹ is hydrogen, R² ismethyl and n is 1 or 2.

The most preferred compounds are:cis-2,3,3a,8-tetrahydro-N,N-dimethyldibenz[c,f]isoxazolo[2,3-a]azepine-2-methanamine,the stereochemically isomeric forms and pharmaceutically acceptable acidaddition salts thereof, and also the N-oxide forms thereof.

Further most preferred are the compounds:cis-2,3,3a,8-tetrahydro-N-methylbenzyl[c,f]isoxazolo[2,3-a]azepine-2-methanamine,the stereochemically isomeric forms and pharmaceutically acceptable acidaddition salts thereof, and also the N-oxide forms thereof.

Among the most preferred compounds mentioned hereinabove,(+)-(A-cis)-2,3,3a,8-tetrahydro-N,N-dimethyldibenz[c,f]isoxazolo[2,3-a]azepinemethanamine(S)-hydroxybutanedioate(1:1) is specifically preferred.

The compounds of formula (I) may generally be prepared by a 1,3-dipolarcycloaddition of a dienophile of formula (III) and an intermediate offormula (II). In the intermediates (II) and (III) and in any otherintermediate mentioned hereinunder, R¹ to R¹⁴ and n are as definedhereinabove, unless otherwise indicated. Said 1,3-dipolar cycloadditionmay conveniently be carded out by mixing the reactants, optionally in areaction-inert solvent such as, for example, an aromatic solvent, e.g.toluene; a ketone, e.g. 4-methyl-2-pentanone; or a mixture of suchsolvents. Stirring and elevated temperatures, or increased pressure mayenhance the rate of the reaction. The reaction of intermediate (I) withintermediate (III) in practice is regioselective yielding to compoundsof formula (I). ##STR5##

In this and the following preparations, the reaction products may beisolated from the reaction medium and, if necessary, further purifiedaccording to methodologies generally known in the art such as, forexample, extraction, crystallization, trituration and chromatography.

The compounds of formula (I) may also be converted into each otherfollowing art-known transformations. For example,

a) a compound of formula (I), wherein R¹ and R² taken together with thenitrogen atom to which they are attached form a radical of formula (b),may be converted into the corresponding primary amine by treatment withhydrazine or aqueous alkali;

b) a compound of formula (I), wherein R¹ or R² istrifluoromethylcarbonyl, may be converted into the corresponding primaryor secondary amine by hydrolysis with aqueous alkali;

c) a compound of formula (I), wherein R¹ or R² is C₁₋₆ alkyl substitutedwith C₁₋₆ alkylcarbonyloxy may be hydrolyzed into a compound of formula(I) wherein R¹ or R² is C₁₋₆ alkyl substituted with hydroxy;

d) a compound of formula (I), wherein R¹ and R² are both hydrogen may bemono- or di-N-alkylated to the corresponding amine form;

e) a compound of formula (I), wherein R¹ and R² are both hydrogen may beN-acylated to the corresponding amide;

f) a compound of formula (I), containing a C₁₋₆ alkyloxycarbonyl groupmay be hydrolyzed to the corresponding carboxylic acid.

The compounds of formula (I) may also be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I) with3-phenyl-2-(phenylsulfonyl)oxaziridine or with an appropriate organic orinorganic peroxide. Appropriate inorganic peroxides comprise, forexample, hydrogen peroxide, alkali metal or earth alkaline metalperoxides, e.g. sodium peroxide, potassium peroxide; appropriate organicperoxides may comprise peroxy acids such as, for example,benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid,e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g.peroxoacetic acid, alkylhydroperoxides, e.g. t-butyl hydroperoxide.Suitable solvents are, for example, water, lower alkanols, e.g. ethanoland the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone,halogenated hydrocarbons, e.g. dichloromethane, and mixtures of suchsolvents.

The intermediates of formula (II) may be prepared by the oxidation of anintermediate of formula (IV) with for example2-benzenesulfonyl-3-phenyl-oxaziridine, hydrogen peroxide, t-butylhydroxyperoxide, or metachloroperbenzoic acid. ##STR6##

Said oxidation is performed in a reaction-inert solvent at temperaturesranging between -20° C. and 50° C., preferably between 0° C. and roomtemperature. Suitable solvents are, for example, water, chlofinatedhydrocarbons, e.g. dichloromethane or chloroform; aromatic hydrocarbons,e.g. toluene; alcohols such as methanol; ketones, e.g.4-methyl-2-pentanone; or a mixture of such solvents. When using peroxideoxidants, the reaction rate may be enhanced by using metallic catalystssuch as, for example, Na₂ WO₄, VO(acetylacetonate)₂, Ti(OBu)₄, or MoO₂(acetylacetonate)₂, optionally under a reaction-inert atmosphere suchas, for example, argon.

Intermediates of formula (IV) may be formed by the reduction of an imineof formula (V) with hydrogen in combination with a suitable catalystsuch as, for example, palladium or platinum supported on for instancecharcoal; in a reaction-inert solvent such as, forexample,-tetrahydrofuran, methanol or a mixture of such solvents. Theformation of an imine of formula (V) is disclosed in J. Chem. Soc. Perk.I (1976), 1279. ##STR7##

Intermediates of formula (IV) may also be prepared by an intramolecularcyclization of an intermediate of formula (VI) by adding a strong acidsuch as, for example, sulfuric acid or phosphoric acid, optionally in areaction-inert solvent, to an intermediate of formula (VI). ##STR8##

Pure stereochemically isomeric forms of the compounds of formula (I) maybe obtained by the application of an-known procedures. Diastereomers maybe separated by physical methods such as selective crystallization andchromatographic techniques, e.g. counter-current distribution, liquidchromatography and the like.

The compounds of formula (I) as prepared in the hereinabove describedprocesses are generally racemic mixtures of enantiomers which can beseparated from one another following art-known resolution procedures.The racemic compounds of formula (I) which are sufficiently basic oracidic may be converted into the corresponding diastereomeric salt formsby reaction with a suitable chiral acid such as, for example,di-1,4-toluolyl-D-tartaric acid, respectively with a suitable chiralbase. Said diastereomeric salt forms are subsequently separated, forexample, by selective or fractional crystallization and the enantiomersare liberated therefrom by alkali or acid. An alternative manner ofseparating the enantiomeric forms of the compounds of formula (I)involves liquid chromatography using a chiral stationary phase. Saidpure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

The compounds of the present invention show affinity for 5-HT₂receptors, particularly for 5-HT_(2A) and 5-HT_(2C) receptors(nomenclature as described by D. Hoyer in "Serotonin (5-HT) inneurologic and psychiatric disorders" edited by M. D. Ferrari andpublished in 1994 by the Boerhaave Commission of the University ofLeiden). Furthermore, the compounds of the present invention showinteresting pharmacological activity in the "mCPP Test on Rats" which isdescribed hereinafter and in the "Elevated and Illuminated Plus MazeTest" which is described in Drug Dev. Res. 18, 119-144 (1989).Additionally, the present compounds show interesting pharmacologicalactivity in the "Tail Suspension Test", and also in the "LSD DrugDiscrimination Test" which is described in Drug Dev. Res. 18, 119-144(1989). Another interesting property of the compounds of formula (I) isthat they suppress amphetamine-induced stereotypical behaviour in rats.

In view of these pharmacological properties, the compounds of formula(I) are useful as therapeutic agents in the treatment or the preventionof central nervous system disorders like anxiety, depression, bipolardisorders, sleep- and sexual disorders, psychosis, schizophrenia,migraine, personality disorders or obsessive-compulsive disorders,social phobias or panick attacks, organic mental disorders, mentaldisorders in children, aggression, memory disorders and attitudedisorders in older people, addiction, obesity, bulimia and similardisorders. In particular, the present compounds may be used asanxiolytics, antidepressants and as agents having the potential tooverrule the addictive properties of drugs of abuse.

The compounds of formula (I) may also serve as therapeutic agents in thetreatment or the prevention of damage to the nervous system caused bytrauma, stroke, neurodegenerative illnesses and the like; cardiovasculardisorders like high blood pressure, thrombosis, stroke, and the like;and gastrointestinal disorders like dysfunction of the motility of thegastrointestinal system and the like. The present compounds may also beuseful as anticonvulsive agents.

In view of the above uses of the compounds of formula (I), it followsthat the present invention also provides a method of treatingwarm-blooded animals suffering from such diseases, said methodcomprising the systemic administration of a therapeutic amount of acompound of formula (I) effective in treating the above describeddisorders.

The present invention thus also relates to compounds of formula (I) asdefined hereinabove for use as a medicine, in particular for use asmedicine to treat the above described disorders.

Those of skill in the treatment of such diseases could determine theeffective therapeutic amount from the test results presentedhereinafter. An effective therapeutic amount would be from about 0.001mg/kg to about 40 mg/kg body weight, more preferably from about 0.003mg/kg to about 10 mg/kg body weight.

For ease of administration, the subject compounds may be formulated intovarious pharmaceutical forms for administration purposes. To prepare thepharmaceutical compositions of this invention, a therapeuticallyeffective amount of the particular compound, optionally in addition saltform, as the active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which may take a wide variety offorms depending on the form of preparation desired for administration.These pharmaceutical compositions are desirably in unitary dosage formsuitable, preferably, for administration orally, rectally,percutaneously, or by parenteral injection. For example, in preparingthe compositions in oral dosage form, any of the usual pharmaceuticalmedia may be employed, such as, for example, water, glycols, offs,alcohols and the like in the case of oral liquid preparations such assuspensions, syrups, elixirs and solutions; or solid carriers such asstarches, sugars, kaolin, lubricants, binders, disintegrating agents andthe like in the case of powders, pills, capsules and tablets. Because oftheir ease in administration, tablets and capsules represent the mostadvantageous oral dosage unit form, in which case solid pharmaceuticalcarriers are obviously employed. For parenteral compositions, thecarrier will usually comprise sterile water, at least in large part,though other ingredients, for example, to aid solubility, may beincluded. Injectable solutions, for example, may be prepared in whichthe carrier comprises saline solution, glucose solution or a mixture ofsaline and glucose solution. Injectable solutions containing compoundsof formula (I) may be formulated in an oil for prolonged action.Appropriate oils for this purpose axe, for example, peanut oil, sesameoil, cottonseed oil, corn oil, soy bean oil, synthetic glycerol estersof long chain fatty acids and mixtures of these and other oils.Injectable suspensions may also be prepared in which case appropriateliquid carriers, suspending agents and the like may be employed. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewettable agent, optionally combined with suitable additives of anynature in minor proportions, which additives do not cause anysignificant deleterious effects on the skin. Said additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as a spot-onor as an ointment. Acid or base addition salts of compounds of formula(I) due to their increased water solubility over the corresponding baseor acid form, are obviously more suitable in the preparation of aqueouscompositions.

In order to enhance the solubility and/or the stability of the compoundsof formula (I) in pharmaceutical compositions, it can be advantageous toemploy α-, β- or γ-cyclodextrins or their derivatives, in particularhydroxyalkyl substituted cyclodextrins, e.g.2-hydroxypropyl-β-cyclodextrin. Also co-solvents such as alcohols mayimprove the solubility and/or the stability of the compounds of formula(I) in pharmaceutical compositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarder. Examples of such dosage unit forms are tablets (including scoredor coated tablets), capsules, pills, powder packets, wafers, injectablesolutions or suspensions, teaspoonfuls, tablespoonfuls and the like, andsegregated multiples thereof.

The following examples are intended to illustrate and not to limit thescope of the present invention.

Experimental part

Hereinunder, "DIPE" means diisopropylether, and "EtOAc" meansethylacetate.

A. Preparation of the intermediates

EXAMPLE 1

Trifluoroacetic acid anhydride (12.7 ml) was added dropwise at 0° C. toa solution of N-methyl-2-propen-1-amine (5 g) and triethylamine (14.7ml) in diethylether (50 ml) and this mixture was stirred at roomtemperature for 6 hours, after which the solvent was evaporated. Theresidue was dissolved in water, extracted with CH₂ Cl₂ and the solventevaporated, yielding 9.4 g (75%) of2,2,2-trifluoro-N-methyl-N-2-propenylacetamide (interm. 1).

Analogously, 1-(2-propenyl)-4-(trifluoroacetyl)piperazine (interm. 2)was prepared.

EXAMPLE 2

a) A mixture of N-methyl-2-propen-1-amine (2.7 ml), ethyl3-bromo-propanoate (4.5 ml) and potassium carbonate (5.8 g) in2-butanone (20 ml) was stirred at 50° C. for 4 hours. The mixture wascooled to room temperature, filtered and the filtrate evaporated. Theresidue was dissolved in water, extracted with CH₂ Cl₂ and the solventevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂ Cl₂ /CH₃ OH 9.75/0.25). The pure fractions werecollected and evaporated, yielding 3 g (63%) of ethylN-methyl-N-2-propenyl-β-alanine (interm. 3).

Similarly, the following intermediates were prepared:

ethyl 4-[methyl(2-propenyl)amino]butanoate (interm. 4); and

ethyl 5-[methyl(2-propenyl)amino]pentanoate (interm. 5).

b) A mixture of intermediate 4 (14 g) in a hydrochloric acid solution(35%) (38 ml), acetic acid (38 ml) and water (19 ml) was stirred andrefluxed for 5 hours. The mixture was cooled on an ice bath and NaOH(50%) was added until the pH was about 6 after which the solvent wasevaporated. The residue was washed with CH₂ Cl₂. The precipitate wasfiltered off and the filtrate evaporated. The syrup (19.4 g) was washedwith toluene and the solvent was evaporated. The product was usedwithout further purification, yielding 15 g (100%) of4-[methyl(2-propenyl)amino]butanoic acid (interm. 6).

Analogously, 5-[methyl(2-propenyl)amino]pentanoic acid (interm. 7) wasprepared from intermediate 5.

EXAMPLE 3

A mixture of 5-hexen-1-ol (5 g) and 8-azaspiro[4.5]decane-7,9-dione (14ml) in triethylamine (150 ml) was cooled on an ice bath.Methane-sulfonyl chloride (8.6 g) in triethylamine (50 ml) was addeddropwise and the mixture was stirred at room temperature for 1 hour. Themixture was filtered off and the filtrate evaporated. Dichloromethane(7.7 g), potassium carbonate (7.6 g) and N,N-dimethylformamide (100 ml)were added to the residue and the mixture was stirred at 160° C.overnight. The mixture was filtered off and the filtrate evaporated. Theresidue was purified by short open column chromatography over silica gel(eluent: CH₂ Cl₂ /CH₃ OH 100/0 to 98/2). The pure fractions werecollected and evaporated, yielding 1.5 g (13%) of8-(5-hexenyl)-8-azaspiro[4.5]decane-7,9-dione (interm. 8).

EXAMPLE 4

a) P₂ O₅ (516.5 g) was added portionwise to H₃ PO₄ (247.5 ml) andstirred under a N₂ flow at room temperature. The mixture was stirred for2 hours at 120° C., then cooled to 50° C. p-Xylene (1810 ml) was added,and stirring was continued for 15 minutes. POCl₃ (83.3 g) was added, andstirring was continued for 10 minutes.N-[2-(phenylmethyl)phenyl]formamide (prepared as described in Helv.Chim. Acta 47(5) 1163-72 (1964)) (37.2 g) was added portionwise. Themixture was stirred for 30 minutes at 60°-70° C. Another portion ofN-[2-(phenylmethyl)phenyl]formamide (74.3 g) was added portionwise, andthe reaction mixture was stirred overnight at 100° C. The reactionmixture was cooled and the p-xylene layer was removed. Water (990 ml)was added slowly. The mixture was cooled with ice-water. A solution ofKOH (1073 g) in water (2200 ml) was added over 2 hours. CH₂ Cl₂ (500 ml)was added dropwise and the mixture was stirred vigorously during 15minutes. The organic layer was separated. The aqueous layer wasextracted twice with CH₂ Cl₂. The combined organic layers were driedwith MgSO₄, filtered off and the solvent evaporated. The residue waspurified by distillation yielding a mixed fraction. The mixed fractionwas repurified twice by distillation, yielding 1.4 g of11H-dibenz[b,e]azepine (interm. 9).

b) A mixture of intermediate 9 (116 g) in methanol (1000 ml) washydrogenated with palladium on activated carbon (10%) (17.7 g) as acatalyst. After uptake of hydrogen (1 eq.), the catalyst was filteredoff and the filtrate evaporated. The residue was stirred up in DIPE(80%), the precipitate was filtered off and dried in vacuo at 45° C. for24 hours, yielding 88.1 g (75.7%) of 6,11-dihydro-5H-dibenz[b,e]-azepine(interm. 10).

In a similar way, there were prepared:

3-chloro-6,11-dihydro-5H-dibenz[b,e]azepine (interm. 11); and

2-chloro-6,11-dihydro-5H-dibenz[b,e]azepine (interm. 12).

c) Bromine (1.3 ml) was added dropwise to a mixture of intermediate 10(5 g) in acetic acid (12 ml) and the mixture was stirred at roomtemperature for 4 hours. The solvent was evaporated and the residue waswashed with NH₄ OH (10%) and dissolved in CH₂ Cl₂. The organic layer wasdried with Na₂ SO₄, filtered off and evaporated. The residue (8 g) waspurified by flash chromatography over silica gel (eluent:hexane/EtOAc9/1). The pure fractions were collected and evaporated, yielding 4 g(56%) of 2 bromo-6,11-dihydro-5H-dibenz[b,e]azepine (interm. 13).

EXAMPLE 5

a) 2-amino-6-chlorobenzoic acid (25 g) dissolved in acetic anhydride(100 ml) was stirred at 120° C. for 2 hours. The mixture was cooled toroom temperature and filtered off. The precipitate was washed with waterand Na₂ CO₃ (10%) and dissolved in CH₂ Cl₂. The solution was dried withNa₂ SO₄, filtered off and evaporated. The residue was crystallized twicefrom benzene, yielding 13 g (46%) of5-chloro-2-methyl-4H-3,1-benzoxazin-4-one; mp. 148.7° C. (interm. 14).

b) Intermediate 14 (20 g) was dissolved in tetrahydrofuran (200 ml) andthe mixture was cooled on an ice water bath under a N₂ atmosphere.Phenylmagnesium bromide (34 ml) in tetrahydrofuran (100 ml) was addeddropwise and the mixture was stirred at 10° C. for 1 hour. The mixturewas quenched with water and HCl (2N) and extracted twice with CH₂ Cl₂.The combined organic layers were dried with Na₂ SO₄, filtered off andthe filtrate evaporated. The residue was purified by short open columnchromatography over silica gel (eluent:CH₂ Cl₂). The pure fractions werecollected and evaporated, yielding 24.5 g (87%) ofN-(2-benzoyl-3-chlorophenyl)-acetamide (interm. 15).

c) Intermediate 15 (20 g) dissolved in acetic acid (700 ml) andhydrochloric acid (175 ml) was stirred and refluxed for 6 hours. Themixture was cooled to room temperature and the solvent evaporated. Theresidue was partitioned between CH₂ Cl₂ and Na₂ CO₃ 10%. The organiclayer was dried with Na₂ SO₄, filtered off and evaporated. The residuewas crystallized from DIPE/EtOAc, yielding 10.5 g (62%) of(2-amino-6-chlorophenyl)phenylmethanone; top. 191.5° C. (interm. 16).

d) Intermediate 16 (10.5 g) and hydrazine hydrate (8.8 ml) weredissolved in 1,2-ethanediol (200 ml) and the mixture was stirred at 200°C. for 2 hours. The mixture was cooled to 60° C., KOH (5.1 g) was addedand the mixture was stirred at 200° C. overnight. The mixture was cooledto room temperature and partitioned between water and CH₂ Cl₂. Theorganic layer was dried with Na₂ SO₄, filtered off and evaporated,yielding 9 g (90%) of 3-chloro-2-(phenylmethyl)-benzenamine (interm.17).

e) A mixture of intermediate 17 (10 g) dissolved in formic acid (100 ml)was stirred and refluxed for 2 hours. The mixture was cooled to roomtemperature and the solvent evaporated. Na₂ CO₃ (10%) was added to theresidue and this aqueous mixture was extracted twice with CH₂ Cl₂. Theorganic layer was dried with Na₂ SO₄, filtered off and evaporated,yielding 9.6 g (85%) of N-[3-chloro-2-(phenylmethyl)phenyl]formamide(interm. 18).

f) Starting from intermediate 18,1-chloro-6,11-dihydro-5H-dibenz[b,e]azepine (interm. 19) was preparedfollowing the procedures as described in example 4.

Analogously, 6,11-dihydro-4-methyl-5H-dibenz[b,e]azepine (interm. 20)was prepared.

EXAMPLE 6

a) A solution of 3-bromobenzenamine (20 g) in 1,2-dichloroethane wasadded dropwise under a N₂ atmosphere to a solution of BCl₃ /xylene (128ml) in 1,2-dichloroethane cooled on ice. Cyanobenzene (12 g) in1,2-dichloroethane and AlCl₃ (17 g) were also added and the mixture wasstirred and refluxed overnight. The mixture was cooled, ice/HCl (2N) wasadded while stirring and the mixture was stirred and heated at 80° C.for 30 minutes. The mixture was cooled, diluted with water and extractedwith CH₂ Cl₂.

The organic layer was dried with Na₂ SO₄, filtered off and evaporated.The residue was purified by short open column chromatography over silicagel (eluent:hexane/CH₂ Cl₂ /EtOAc 6/3/1). The pure fractions werecollected and evaporated, yielding 13 g (41%) of(4-bromo-2-aminophenyl)phenyl-methanone (interm. 21).

b) Starting from intermediate 21,3-bromo-6,11-dihydro-5H-dibenz[b,e]azepine (interm. 22) was prepared inan analogous manner as intermediate 19 was prepared from intermediate 16as described in example 5d, 5e and 5f.

Analogously, there were prepared:

6,11-dihydro-3-methyl-5H-dibenz[b,e]azepine (interm. 23);

6,11-dihydro-2-methyl-5H-dibenz[b,e]azepine (interm. 24);

6,11-dihydro-10-methyl-5H-dibenz[b,e]azepine (interm. 25); and

6,11-dihydro-8-methyl-5H-dibenz[b,e]azepine (interm. 26).

EXAMPLE 7

2-[[(4-chlorophenyl)methyl]amino]benzenemethanol (6.7 g) (prepared asdescribed in J. Chem. Soc. Chem. Commun., 1989 (1), 44-5) was cooledunder a N₂ atmosphere to -40° C. Sulfuric acid (35 ml) was addeddropwise keeping the temperature at about -10° C. and the mixture wasstirred at room temperature for 1 hour. The mixture was poured into icewater and basified carefully with KOH. The mixture was filtered off andthe precipitate was washed with water and CH₂ Cl₂. The filtrate and thewashings were extracted, dried with Na₂ SO₄, filtered off andevaporated, yielding 5.8 g (95%) of9-chloro-6,11-dihydro-5H-dibenz-[b,e]azepine (interm. 27).

Analogously, 3-fluoro-6,11-dihydro-5H-dibenz[b,e]azepine (interm. 28)was prepared.

EXAMPLE 8

Procedure 1

3-Phenyl-2-(phenylsulfonyl)oxaziridine (18.7 g) was added portionwise toa solution of intermediate 10 (7 g) in CHCl₃ (120 ml) and wassubsequently stirred at room temperature for 2 hours. The solvent wasevaporated and the residue was purified by short open columnchromatography over silica gel (eluent: CH₂ Cl₂ /CH₃ OH 97.5/2.5). Thepure fractions were collected and evaporated, yielding 10 g (80%) of11H-dibenz[b,e]azepine,5-oxide; mp. 109.2° C. (interm. 29).

Procedure 2

A solution of intermediate 10 (50 g) in CH₂ Cl₂ (1282 ml) was stirredand cooled to ±10° C. A solution of metachloroperbenzoic acid (115.6 g)in CH₂ Cl₂ (2430 ml) was added dropwise at <15° C. The reaction mixturewas stirred for 1 hour. The mixture was extracted with a 10% aqueous Na₂SO₃ solution (1 liter), then with a 5% aqueous Na₂ CO₃ solution. Theorganic phase was dried, filtered, and the solvent was evaporated,yielding 53.5 g (quantitative yield) of 11H-dibenz[b,e]azepine,5-oxide(interm 29).

Analogous to procedure 2, 11-methylene-11H-dibenz[b,c]azepine,5-oxidewas prepared (interm. 73). The compounds listed in Table 1 were preparedanalogously to procedure 1.

                                      TABLE 1                                     __________________________________________________________________________     ##STR9##                                                                     Int.                                     physical data                        No.                                                                              R.sup.3                                                                          R.sup.4                                                                           R.sup.5                                                                          R.sup.6                                                                           R.sup.7                                                                          R.sup.8                                                                          R.sup.9                                                                          R.sup.10                                                                           R.sup.11                                                                          R.sup.12                                                                         R.sup.13                                                                         (mp. in °C.)                  __________________________________________________________________________    29 H  H   H  H   H  H  H  H    H   H  H  109.2                                30 H  Cl  H  H   H  H  H  H    H   H  H  --                                   31 H  H   Cl H   H  H  H  H    H   H  H  --                                   32 H  H   H  Cl  H  H  H  H    H   H  H  --                                   33 H  Br  H  H   H  H  H  H    H   H  H  --                                   34 CH.sub.3                                                                         H   H  H   H  H  H  H    H   H  H  --                                   35 H  CH.sub.3                                                                          H  H   H  H  H  H    H   H  H  --                                   36 H  H   CH.sub.3                                                                         H   H  H  H  H    H   H  H  --                                   37 H  H   H  H   H  H  CH.sub.3                                                                         H    H   H  H  --                                   38 H  H   H  H   H  H  H  H    CH.sub.3                                                                          H  H  --                                   39 H  H   H  H   H  H  H  Cl   H   H  H  --                                   40 H  F   H  H   H  H  H  H    H   H  H  --                                   41 H  H   Br H   H  H  H  H    H   H  H  --                                   42 H  H   H  H   H  H  H  H    H   H  CH.sub.3                                                                         141.7                                43 H  H   H  H   CH.sub.3                                                                         CH.sub.3                                                                         H  H    H   H  H  --                                   44 H  H   H  CH.sub.3                                                                          H  H  H  H    H   H  H  --                                   45 H  H   H  H   CH.sub.3                                                                         H  H  H    H   H  H  --                                   46 H  H   H  F   H  H  H  H    H   H  H  --                                   47 H  H   H  H   H  H  F  H    H   H  H  --                                   48 H  H   H  H   H  H  H  F    H   H  H  --                                   49 H  H   H  H   H  H  H  H    F   H  H  --                                   50 H  H   H  H   H  H  H  H    H   F  H  --                                   51 H  H   H  H   H  H  H  CF.sub.3                                                                           H   H  H  --                                   52 H  H   H  H   H  H  H  H    H   CF.sub.3                                                                         H  --                                   53 H  H   H  H   H  H  Cl H    H   H  H  --                                   54 H  H   H  H   H  H  H  H    Cl  H  H  --                                   55 H  Cl  Cl H   H  H  H  H    H   H  H  --                                   56 H  Cl  H  H   H  H  Cl H    H   H  H  --                                   57 H  Cl  H  H   H  H  H  H    Cl  H  H  --                                   58 H  Cl  F  H   H  H  H  H    H   H  H  --                                   59 H  F   H  H   H  H  Cl H    H   H  H  --                                   60 H  F   H  H   H  H  H  H    Cl  H  H  --                                   61 H  F   H  H   H  H  F  H    H   H  H  --                                   62 H  F   H  H   H  H  H  H    F   H  H  --                                   63 H  Cl  H  H   H  H  Cl Cl   H   H  H  --                                   64 H  Cl  H  H   H  H  H  Cl   Cl  H  H  --                                   65 H  H   H  Br  H  H  H  H    H   H  H  --                                   66 H  H   H  H   H  H  Br H    H   H  H  --                                   67 H  H   H  H   H  H  H  Br   H   H  H  --                                   68 H  H   H  H   H  H  H  H    Br  H  H  --                                   69 H  OCH.sub.3                                                                         H  H   H  H  H  H    H   H  H  --                                   70 H  H   H  OCH.sub.3                                                                         H  H  H  H    H   H  H  --                                   71 H  H   H  H   H  H  H  H    OCH.sub.3                                                                         H  H  --                                   72 H  H   H  H   IH IH H  N(CH.sub.3).sub.2                                                                  H   H  H  --                                   __________________________________________________________________________

B. Preparation of compounds of formula (I)

EXAMPLE 9

A mixture of intermediate 29 (2.7 g) and N,N-dimethyl-2-propen-1-amine(3 ml) in toluene (60 ml) was stirred at 100° C. overnight. The solventwas evaporated and the residue was purified by flash chromatography oversilica gel (eluent: CH₂ Cl₂ /CH₃ OH 95/5). The pure fractions werecollected and evaporated. The residue (3.1 g), containing the free base(±)-cis-2,3,3a,8-tetrahydro-N,N-dimethyldibenz[c,f]isoxazolo[2,3-a]-azepine-2-methanamine(comp. 59), was converted into the oxalic acid salt (1:1) in C₂ H₅ OH atroom temperature, yielding 2.6 g (52%) of(±)-cis-2,3,3a,8-tetrahydro-N,N-dimethyldibenz[c,f]isoxazolo-[2,3-a]azepine-2-methanamineethanedioate(1:1); mp. 139.5° C. (comp. 1).

EXAMPLE 10

Following the same procedure as in example 9, but using4-methyl-2-pentanone as solvent, there was prepared(±)-cis-2,3,3a,8-tetrahydro-2-(1-pyrrolidinyl-methyl)dibenz[c,f]isoxazolo[2,3-a]azepineethanedioate(1:1); mp. 167.2° C. (comp. 2).

EXAMPLE 11

Using the same procedure as in example 9, but stirring the startingmaterials without solvent in a Parr Pressure Vessel at 100° C.overnight, there was prepared(±)-(cis+trans)-2,3,3a,8-tetrahydro-N,N,3a-trimethyldibenz[c,f]isoxazolo[2,3-a]azepine-2-methanamine(comp. 3).

EXAMPLE 12

Compound 59 (the free base form of compound 1), as prepared in example9, was converted to the fumarate salt (1:1) by adding dropwise anethanolic solution of fumaric acid (0.215 g/ml) to a mixture, cooled onan ice-bath, of the free base form in a mixture of ethanol (8 ml) anddiethylether (30 ml). The formed precipitate was filtered off and driedin vacuo, yielding 1 g (71%) of(±)-cis-2,3,3a,8-tetrahydro-N,N-dimethyl-dibenz[c,f]isoxazolo[2,3-a]azepine-2-methanamine(E)-2-butenedioate(1:1); mp. 148.9° C. (comp. 4).

EXAMPLE 13

a) Compound 59 (the free base form of compound 1), as prepared inexample 9, was separated and purified by column chromatography over aChiralcel OJ column (Daicel, 250 g, 20 μm, length: 23 cm; detection at200 nm; flow: 40 ml/min; eluent: hexane/ethanol 80/20; injection volume:25 ml).

1) The desired (A-cis)-fractions were collected and the solvent wasevaporated. The residue (6.8 g) was dissolved in ethanol (50 ml),stirred at room temperature and converted into the oxalic acid salt(1:1) with a solution of oxalic acid (2.94 g) in ethanol (50 ml). Thedesired compound crystallized out and the precipitate was filtered offand dried, yielding 5.5 g (24.7%) of(+)-(A-cis)-2,3,3a,8-tetrahydro-N,N-diimethyldibenz[c,f]isoxazolo-[2,3-a]azepine-2-methanamineethanedioate(1:1); mp. 167.0° C. (comp. 5).

2) The desired (B-cis)-fractions were treated in an analogous manner asthe (A-cis)-fractions, yielding 3.4 g (15.2%) of(-)-(B-Cis)-2,3,3a,8-tetrahydro-N,N-dimethyldibenz-[c,f]isoxazolo[2,3-a]azepine-2-methanamineethanedioate(1:1); mp. 152.4° C. (comp. 6).

b) Compound 1, as prepared in example 9, was separated and purified bycolumn chromatography over a Chiralcel OJ column (Daicel, 250 g, 20 μm,length: 23 cm; detection at 200 nm; flow: 40 ml/min; eluent:hexane/ethanol 80/20; injection: compound 1 (0.55 g) was dissolved inn-hexane/ethanol (1:1) (50 ml); injection volume: 20 ml; concentration:11.00 mg/ml). Two desired fraction groups (1) and (2) were collected andtheir solvent was evaporated, yielding 0.2 g (47.5%)(A-cis)-2,3,3a,8-tetrahydro-N,N-dimethyldibenzc,flisoxazolo-[2,3-a]azepine-2-methanamine (comp. 7) and 0.19 g offraction (2). Fraction (2) contained an impurity (20%) which wasseparated by reversed-phase column chromatography over RP-Kromasil C-18(1 inch; eluent: (0.2% NH₄ OAc in H₂ O)/CH₃ OH 30/70). The purefractions were collected and the organic solvent was evaporated at roomtemperature. The aqueous residue was extracted with CHCl₃. The separatedorganic layer was evaporated, yielding 0.110 g (26.1%)(B-cis)-2,3,3a,8-tetrahydro-N,N-dimethyldibenz[c,f]isoxazolo-[2,3-a]azepine-2-methanamine(comp. 8).

EXAMPLE 14

A mixture of(±)-cis-2-[(2,3,3a,8-tetrahydrodibenz[c,f]isoxazolo[2,3-a]azepin-2-yl)methyl]-1H-isoindole-1,3(2H)-dione(4 g), prepared following the procedure of example 1, and hydrazinehydrate (0.5 ml) in ethanol (80 ml) was stirred at 80° C. for 4 hours.The precipitate was filtered off and purified by open columnchromatography over silica gel (eluent: CH₂ Cl₂ /2-propanone 8/2). Thepure fractions were collected and evaporated. The residue (1.6 g) wasconvened into the oxalic acid salt (1:1) in C₂ H₅ OH at roomtemperature. The residue (0.8 g) was purified by column chromatographyover silica gel (eluent: CH₂ Cl₂ /CH₃ OH 97.5/2.5 to 95/5). The purefractions were collected and evaporated, yielding 0.6 g (22%) of(±)-cis-2,3,3a,8-tetrahydrodibenz[c,f]isoxazolo-[2,3-a]azepine-2-methanamine(comp. 9).

EXAMPLE 15

A mixture of(±)-cis-2,2,2-trifluoro-N-methyl-N-[(2,3,3a,8-tetrahydrodibenz[c,f]-isoxazolo[2,3-a]azepin-2-yl)methyl]acetamide(4 g), prepared following the procedure of example 9, and sodiumhydroxide (1.06 g) in methanol (60 ml) and water (12 ml) was stirred at60° C. for 3 hours. The solvent was evaporated, the residue was dilutedwith water and extracted with CH₂ Cl₂. The organic layer was dried withNa₂ SO₄, filtered off and evaporated. The residue (3.9 g) was purifiedby short open column chromatography over silica gel (eluent: CH₂ Cl₂/CH₃ OH 95/5). The pure fractions were collected and evaporated. Theresidue was convened into the oxalic acid salt (1:1) in C₂ H₅ OH at roomtemperature, yielding 3.2 g (82%) of(±)-cis-2,3,3a,8-tetrahydro-N-methyldibenz[c,f]-isoxazolo[2,3-a]azepine-2-methanamineethanedioate(1:1); mp. 134.0° C. (comp. 10).

EXAMPLE 16

A mixture of intermediate 29 (54.5 g) and N,N-dimethyl-2-propen-1-amine(35.8 g) in toluene (1000 ml) was stirred overnight at 100° C. Thesolvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂ Cl₂ /CH₃ OH 97/3). Thedesired fractions were collected and the solvent was evaporated. Theresidue was purified and separated into its enantiomers by columnchromatography over Chiralcel OJ (eluent: hexane/ethanol 90/10). Thepure fractions were collected and the solvent was evaporated. Theresidue was dissolved in ethanol (100 ml; p.a.) and converted into the(S)-malic acid salt (1:1) by addition of (-)-(S)-malic acid (9 g). Themixture was stirred overnight and the resulting precipitate was filteredoff, dried, stirred in ethanol (100 ml), washed with DIPE, and dried,yielding 18.8 g of(+)-(A-cis)-2,3,3a,8-tetrahydro-N,N-dimethyldibenz[c,f]isoxazolo[2,3-a]azepinemethanamine(S)-hydroxybutanedioate(1:1); mp. 154.2° C.; α=50.41° at 20° C. for100.58 mg in 10 ml methanol (comp. 58).

EXAMPLE 17

A solution of (+)-(R)-malic acid (0.67 g) in ethanol (10 ml) was addedto a solution of compound 59 (1.47 g) in ethanol (10 ml), stirred atroom temperature. The resulting clear solution was allowed tocrystallize out. The precipitate was filtered off and dried (vacuum; 50°C.; 24 hours). This fraction was recrystallized from ethanol (15 ml),filtered off and dried (vacuum; 50° C.), yielding 0.76 g(±)-cis-2,3,3a,8-tetrahydro-N,N-dimethyldibenz[c,f]isoxazolo[2,3-a]azepinemethanamine(R)-hydroxybutanedioate (1:1) (35.5%); mp. 138.6° C.; α=13.86° at 20° C.for 10.10 mg in 10 ml methanol (comp. 57).

EXAMPLE 18

Compound 58 (2.1 g) was converted into the free base by treatment withaqueous ammonia (at 0° C.). This mixture was extracted with CH₂ Cl₂ (100ml). The separated organic layer was dried, filtered and the filtratewas combined with 3-phenyl-2-(phenylsulfonyl)oxaziridine (1.3 g). Thismixture was stirred for 24 hours at room temperature. The solvent wasevaporated and the residue was purified by column chromatography oversilica gel (eluent: CH₂ Cl₂ /(CH₃ OH/NH₃) 90/10). The pure fractionswere collected and the solvent was evaporated. The residue wastriturated in DIPE, filtered off and dried, yielding 0.85 g (55%) of(A-cis)-2,3,3a,8-tetrahydro-N,N-dimethyldibenz[c,f]isoxazolo[2,3-a]azepinemethanamine,N-oxidemonohydrate; mp. 170° C. (comp. 96).

Tables 2 through 6 list compounds that were prepared in a similar way asin one of the hereinabove mentioned examples.

                                      TABLE 2                                     __________________________________________________________________________     ##STR10##                                                                    Co                                                                              Ex.                                                                         No                                                                              No R.sup.3                                                                          R.sup.4                                                                           R.sup.5                                                                          R.sup.6                                                                           R.sup.9                                                                          R.sup.10                                                                           R.sup.11                                                                          R.sup.12                                                                         physical data (mp. in                       __________________________________________________________________________                                      °C.)                                  1                                                                               9 H  H   H  H   H  H    H   H  (±)-cis/(COOH).sub.2 /139.5               4                                                                              12 H  H   H  H   H  H    H   H  (±)-cis/fumaric acid/148.9                5                                                                              13b                                                                              H  H   H  H   H  H    H   H  (+)-(A-cis)/(COOH).sub.2 /167.0              6                                                                              13b                                                                              H  H   H  H   H  H    H   H  (-)-(B-cis)/(COOH).sub.2 /152.4              7                                                                              13a                                                                              H  H   H  H   H  H    H   H  (A-cis)                                      8                                                                              13a                                                                              H  H   H  H   H  H    H   H  (B-cis)                                     57                                                                              17 H  H   H  H   H  H    H   H  (-)-cis/(R)-malic acid/138.6                58                                                                              16 H  H   H  H   H  H    H   H  (+)-(A-cis)/(S)-malic                                                         acid/154.2                                  59                                                                               9 H  H   H  H   H  H    H   H  (±)-cis                                  60                                                                              17 H  H   H  H   H  H    H   H  (-)-(A-cis)/[R-(R*,R*)]-2,3-                                                  bis[(4-methylbenzoyl)oxy]-                                                    butanedioic acid/155.2                      61                                                                              13a                                                                              H  H   H  H   H  H    H   H  (A-trans)/(S)-malic                                                           acid/150.9                                  62                                                                              13a                                                                              H  H   H  H   H  H    H   H  (B-trans)/(S)-malic                                                           acid/148.2                                  11                                                                               9 Cl H   H  H   H  H    H   H  cis/(COOH).sub.2 /141.9                     12                                                                               9 H  Cl  H  H   H  H    H   H  ±-cis/(COOH).sub.2 /185.3                13                                                                               9 H  H   Cl H   H  H    H   H  ±-cis/(COOH).sub.2 /172.2                14                                                                               9 H  H   H  Cl  H  H    H   H  cis/(COOH).sub.2 /177.6                     63                                                                               9 H  H   H  H   Cl H    H   H  cis/(COOH).sub.2 /157.5                     24                                                                               9 H  H   H  H   H  Cl   H   H  cis/(COOH).sub.2 /171.8                     15                                                                               9 H  H   H  H   H  H    Cl  H  cis/(COOH).sub.2 /182.6                     16                                                                               9 H  Br  H  H   H  H    H   H  cis/(COOH).sub.2 /170.5                     27                                                                               9 H  H   Br H   H  H    H   H  cis/181.1                                   64                                                                               9 H  H   Br H   H  H    H   H  (+)-(A-cis)/73.5                            65                                                                               9 H  H   Br H   H  H    H   H  (-)-(B-cis)/74.1                            66                                                                               9 H  H   H  Br  H  H    H   H  cis/(COOH).sub.2 /166.3                     67                                                                               9 H  H   H  H   Br H    H   H  cis/(COOH).sub.2 /158.3                     68                                                                               9 H  H   H  H   H  Br   H   H  cis/(COOH).sub.2 /165.0                     69                                                                               9 H  H   H  H   H  H    Br  H  cis/90.2                                    17                                                                               9 CH.sub.3                                                                         H   H  H   H  H    H   H  (cis+trans)/(COOH).sub.2 /                                                    172.8                                       18                                                                               9 H  CH.sub.3                                                                          H  H   H  H    H   H  cis/(COOH).sub.2 /149.4                     19                                                                               9 H  H   CH.sub.3                                                                         H   H  H    H   H  cis/(COOH).sub.2 /137.2                     70                                                                               9 H  H   H  CH.sub.3                                                                          H  H    H   H  cis/(COOH).sub.2 /174.7                     20                                                                               9 H  H   H  H   CH.sub.3                                                                         H    H   H  cis/(COOH).sub.2 /163.1                     21                                                                               9 H  H   H  H   H  CH.sub.3                                                                           H   H  cis/(COOH).sub.2 /162.9                     22                                                                               9 H  H   H  H   H  H    CH.sub.3                                                                          H  cis/(COOH).sub.2 /158.4                     23                                                                               9 H  H   H  H   H  H    H   CH.sub.3                                                                         (cis+trans)/(COOH).sub.2 /                                                    189.1                                       25                                                                               9 H  F   H  H   H  H    H   H  cis/(COOH).sub.2 /172.7                     26                                                                               9 H  H   F  H   H  H    H   H  cis/(COOH).sub.2 /157.9                     71                                                                               9 H  H   H  F   H  H    H   H  cis/(COOH).sub.2 /175.7                     72                                                                               9 H  H   H  H   F  H    H   H  cis/(COOH).sub.2 /151.0                     73                                                                               9 H  H   H  H   H  F    H   H  cis/(COOH).sub.2 /157.3                     74                                                                               9 H  H   H  H   H  H    F   H  cis/(COOH).sub.2 /171.4                     75                                                                               9 H  H   H  H   H  H    H   F  cis/(COOH).sub.2 /190.6                     28                                                                               9 H  H   H  H   CF.sub.3                                                                         H    H   H  cis/(COOH).sub.2 /165.4                     76                                                                               9 H  H   H  H   H  CF.sub.3                                                                           H   H  cis/(COOH).sub.2 /168.1                     29                                                                               9 H  H   H  H   H  H    CF.sub.3                                                                          H  cis/(COOH).sub.2 /170.6                     77                                                                               9 H  H   H  H   H  H    H   CF.sub.3                                                                         cis/(COOH).sub.2 /176.7                     78                                                                               9 H  H   H  OCH.sub.3                                                                         H  H    H   H  cis/(COOH).sub.2 /176.9                     79                                                                               9 H  OCH.sub.3                                                                         H  H   H  H    H   H  cis/102.2                                   80                                                                               9 H  H   H  H   H  H    OCH.sub.3                                                                         H  cis/(COOH).sub.2 /163.2                     81                                                                               9 H  H   H  H   H  N(CH.sub.3).sub.2                                                                  H   H  cis/3/2(COOH).sub.2 /114.9                  82                                                                               9 H  Cl  Cl H   H  H    H   H  cis/110.6                                   83                                                                               9 H  Cl  H  H   Cl H    H   H  cis/malic acid/149.7                        84                                                                               9 H  Cl  H  H   H  H    Cl  H  cis/(COOH).sub.2 /196.7                     85                                                                               9 H  Cl  H  H   Cl Cl   H   H  cis/(COOH).sub.2 /195.0                     86                                                                               9 H  Cl  H  H   H  Cl   Cl  H  cis/(COOH).sub.2 /192.6                     87                                                                               9 H  Cl  F  H   H  H    H   H  cis/(COOH).sub.2 /264.3                     88                                                                               9 H  F   H  H   Cl H    H   H  cis/(COOH).sub.2 /182.9                     89                                                                               9 H  F   H  H   H  H    Cl  H  cis/(COOH).sub.2 /195.7                     90                                                                               9 H  F   H  H   F  H    H   H  cis/(COOH).sub.2 /154.9                     91                                                                               9 H  F   H  H   H  H    F   H  cis/(COOH).sub.2 /171.1                     __________________________________________________________________________

                                      TABLE 3                                     __________________________________________________________________________     ##STR11##                                                                    Co.                                                                              Ex                                phys. data                               No No R.sup.1  R.sup.2                                                                          R.sup.4                                                                         R.sup.7                                                                          R.sup.8                                                                          R.sup.11                                                                         R.sup.13                                                                         R.sup.14                                                                         n (mp. in °C.)                      __________________________________________________________________________     3 11 CH.sub.3 CH.sub.3                                                                          H H  H  H  CH.sub.3                                                                         H  1 (cis+trans)                              9 14 H        H   H H  H  H  H  H  1 ±-cis                                10 15 H        CH.sub.3                                                                          H H  H  H  H  H  1 ±-cis/(COOH).sub.2 /                                                       134.0                                   30  9 CH.sub.3 CH.sub.3                                                                          H H  H  H  H  H  2 ±-cis/(COOH).sub.2 /                                                       150.1                                   31  9 CH.sub.3 CH.sub.3                                                                          H H  H  H  H  H  3 ±-cis/(COOH).sub.2 /                                                       132.7                                   32  9 CH.sub.3 CH.sub.3                                                                          H H  H  H  H  H  4 ±-cis/(COOH).sub.2 /                                                       142.9                                   33  9 C.sub.2 H.sub.5                                                                        CH.sub.3                                                                          H H  H  H  H  H  1 cis/(COOH).sub.2 /                                                            148.4                                   34 15 (CH.sub.2).sub.2 -OH                                                                   CH.sub.3                                                                          H H  H  H  H  H  1 ±-cis/(COOH).sub.2 /                                                       148.6                                   35  9 C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                                                                   H H  H  H  H  H  1 ±-cis/(COOH).sub.2 /                                                       174.0                                   36  9 i-C.sub.3 H.sub.7                                                                      i-C.sub.3 H.sub.7                                                                 H H  H  H  H  H  1 ±-cis/65.8                           37  9 (CH.sub.2).sub.3 -COOH                                                                 CH.sub.3                                                                          H H  H  H  H  H  1 ±-cis/130.5                          38  9 (CH.sub.2).sub.4 -COOH                                                                 CH.sub.3                                                                          H H  H  H  H  H  1 ±-cis/155.5                          39  9 (CH.sub.2).sub.2 OCOCH.sub.3                                                           CH.sub.3                                                                          H H  H  H  H  H  1 ±-cis/(COOH).sub.2 /                                                       142.6                                   92  9 (CH.sub.2).sub.2 OCOCH.sub.3                                                           CH.sub.3                                                                          Cl                                                                              H  H  Cl H  H  1 cis/(COOH).sub.2 /                                                            170.5                                   40  9 COCF.sub.3                                                                             CH.sub.3                                                                          H H  H  H  H  H  1 ±-cis/119.1                          93  9 CH.sub.3 CH.sub.3                                                                          H CH.sub.3                                                                         H  H  H  H  1 (COOH).sub.2 /128.1                     41  9 CH.sub.3 CH.sub.3                                                                          H CH.sub.3                                                                         CH.sub.3                                                                         H  H  H  1 cis/(COOH).sub.2 /                                                            166.6                                   42  9 CH.sub.3 CH.sub.3                                                                          H H  H  H  H  CH.sub.3                                                                         1 ±-cis/(COOH).sub.2 /                                                       165.0                                   43  9 CH.sub.3 CH.sub.3                                                                          H H  H  H  H  CH.sub.3                                                                         1 ±-trans/(COOH).sub.2 /                                                     112.2                                   94  9 CH.sub.3 CH.sub.3                                                                          Cl                                                                              H  H  Cl H  CH.sub.3                                                                         1 cis/(COOH).sub.2 /                                                            199.2                                   95  9 CH.sub.3 CH.sub.3                                                                          Cl                                                                              H  H  Cl H  CH.sub.3                                                                         1 trans/67.7                              97  9 CH.sub.3 CH.sub.3                                                                          H ═CH.sub.2 *                                                                     H  H  H  1 ±/(COOH).sub.2 /                                                           170.0                                   __________________________________________________________________________     *R.sup.7 and R.sup.8 are taken together                                  

                  TABLE 4                                                         ______________________________________                                         ##STR12##                                                                    Co. No.                                                                              Ex. No.  R.sup.23    physical data (mp. in °C.)                 ______________________________________                                        44     15       H           ±-cis/(COOH).sub.2 /278.9                      45     9        CH.sub.3    ±-cis/(COOH).sub.2 /196.6                      46     9        COCF.sub.3  ±-cis/(COOH).sub.2 /149.4                      47     9        3-chlorophenyl                                                                            ±-cis/59.1                                     ______________________________________                                    

                  TABLE 5                                                         ______________________________________                                         ##STR13##                                                                    Co. No.                                                                              Ex. No.    R.sup.4                                                                             n     physical data (mp. in °C.)               ______________________________________                                        48     9          H     1     ±-cis/150.8                                  49     9          F     1     cis/74.7                                        50     9          H     2     ±-cis/190.0                                  51     9          H     4     ±-cis                                        ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                         ##STR14##                                                                    Co.  Ex.                        physical data                                 No.  No.    R.sup.14                                                                             Q            (mp. in °C.)                           ______________________________________                                         2   10     H      1-pyrrolidinyl                                                                             cis/(COOH).sub.2 /167.2                       52   9      H      1-piperidinyl                                                                              ±-cis/(COOH).sub.2 /198.8                  53   9      CN     1-piperidinyl                                                                              ±-trans/127.8                              54   9      H      hexahydro-1H-azepin-                                                                       ±-cis/(COOH).sub.2 /188.0                                     1-yl                                                       55   9      H      1,3-dihydro-2H-                                                                            ±-cis/150.0                                                   isoindol-2-yl                                              56   9      H      1,3-dihydro-1,3-dioxo-                                                                     ±-cis/184.1                                                   2H-isoindol-2-yl                                           96   18     H                                                                                     ##STR15##   (A-cis)                                       ______________________________________                                    

C. Pharmacological example

EXAMPLE 19

"mCPP Test on Rats"

Rats were treated with the test compound at a dose varying between0.0025 mg/kg and 40 mg/kg body weight, at pre-test time T varyingbetween 5 and 480 minutes, and with 1 mg/kg mCPP(metachlorophenylpiperazine), injected intravenously, 15 minutes priorto the test. After pre-test time T elapsed, treated rats were submittedto the "Open Field Test on Rats" as described in Drug Dev. Res. 18,119-144 (1989), but using an infra-red light source instead of aKleverlux® (12 V/20 W) light source. A dose at which 40% of the testedrats showed suppression of the mCPP induced effects, i.e.mCPP-antagonism, was defined as an active dose. The activity range of atest compound was measured by the ratio of the HAD (highest active dose)over the LAD (lowest active dose). The compounds with number 1, 4-7, 10,15, 18, 25, 26, 30, 39, 57, 58, 77, 84, 89 and 91 had a ratio (HAD overLAD) of 16 or more at a pre-test time T being 60 minutes. Also at apre-test time T of 60 minutes, the compounds with number 2, 8, 11-14,16, 19, 21, 23, 24, 27, 29, 35, 42-45, 47, 48, 52, 54, 55, 59-62, 65-75,78, 79, 87, 88, 90 and 92-94 showed mCPP-antagonism at least at onetested dose.

D. Composition examples

"Active ingredient" (A.I.) as used throughout these examples relates toa compound of formula (I), a pharmaceutically acceptable acid additionsalt, a stereochemically isomeric form thereof or a N-oxide formthereof.

EXAMPLE 20

ORAL DROPS

500 Grams of the A.I. was dissolved in 0.5 l of 2-hydroxypropanoic acidand 1.5 l of the polyethylene glycol at 60°˜80° C. After cooling to30°˜40° C. there were added 35 l of polyethylene glycol and the mixturewas stirred well. Then there was added a solution of 1750 grams ofsodium saccharin in 2.5 l of purified water and while stirring therewere added 2.5 l of cocoa flavor and polyethylene glycol q.s. to avolume of 50 l, providing an oral drop solution comprising 10 mg/ml ofA.I. The resulting solution was filled into suitable containers.

EXAMPLE 21

ORAL SOLUTION

9 Grams of methyl 4-hydroxybenzoate and 1 gram of propyl4-hydroxybenzoate were dissolved in 4 1 of boiling purified water. In 3l of this solution were dissolved first 10 grams of2,3-dihydroxybutanedioic acid and thereafter 20 grams of the A.I. Thelatter solution was combined with the remaining part of the formersolution and 12 l 1,2,3-propanetriol and 3 l of sorbitol 70% solutionwere added thereto. 40 Grams of sodium saccharin were dissolved in 0.5 lof water and 2 ml of raspberry and 2 ml of gooseberry essence wereadded. The latter solution was combined with the former, water was addedq.s. to a volume of 20 l providing an oral solution comprising 5 mg ofthe active ingredient per teaspoonful (5 ml). The resulting solution wasfilled in suitable containers.

EXAMPLE 22

FILM-COATED TABLETS

Preparation of tablet core

A mixture of 100 grams of the A.I., 570 grams lactose and 200 gramsstarch was mixed well and thereafter humidified with a solution of 5grams sodium dodecyl sulfate and 10 grams polyvinylpyrrolidone in about200 ml of water. The wet powder mixture was sieved, dried and sievedagain. Then there was added 100 grams microcrystalline cellulose and 15grams hydrogenated vegetable oil. The whole was mixed well andcompressed into tablets, giving 10.000 tablets, each containing 10 mg ofthe active ingredient.

Coating

To a solution of 10 grams methyl cellulose gin 75 ml of denaturatedethanol there was added a solution of 5 grams of ethyl cellulose in 150ml of dichloromethane. Then there were added 75 ml of dichloromethaneand 2.5 ml 1,2,3-propanetriol. 10 Grams of polyethylene glycol wasmolten and dissolved in 75 ml of dichloromethane. The latter solutionwas added to the former and then there were added 2.5 grams of magnesiumoctadecanoate, 5 grams of polyvinylpyrrolidone and 30 ml of concentratedcolour suspension and the whole was homogenated. The tablet cores werecoated with the thus obtained mixture in a coating apparatus.

EXAMPLE 23

INJECTABLE SOLUTION

1.8 Grams methyl 4-hydroxybenzoate and 0.2 grams propyl4-hydroxybenzoate were dissolved in about 0.5 l of boiling water forinjection. After cooling to about 50° C. there were added while stirring4 grams lactic acid, 0.05 grams propylene glycol and 4 grams of the A.I.The solution was cooled to room temperature and supplemented with waterfor injection q.s. ad 1 l, giving a solution comprising 4 mg/ml of A.I.The solution was sterilized by filtration and filled in sterilecontainers.

We claim:
 1. A compound of the formula: ##STR16## a pharmaceuticallyacceptable acid or base addition salt thereof, or a stereochemicallyisomeric form thereof, or an N-oxide form thereof, wherein:R¹ and R²each independently are hydrogen; C₁₋₆ alkyl; C₁₋₆ alkylcarbonyl;trihalomethylcarbonyl; C₁₋₆ alkyl substituted with hydroxy, C₁₋₆alkyloxy, carboxyl, C₁₋₆ alkylcarbonyloxy, C₁₋₆ alkyloxycarbonyl oraryl; or R¹ and R² taken together with the nitrogen atom to which theyare attached may form a morpholinyl ring or a radical of the formula:##STR17## wherein: R¹⁵, R¹⁶, R¹⁷ and R¹⁸ each independently are hydrogenhalo, trifluoromethyl or C₁₋₆ alkyl; m is 1, 2 or 3; R¹⁹, R²⁰, R²¹ andR²² each independently are hydrogen or C₁₋₆ alkyl; or R²¹ and R²² takentogether may form a bivalent radical C₄₋₅ alkanediyl; R²³ is hydrogen;C₁₋₆ alkyl; C₁₋₆ alkylcarbonyl; trihalomethylcarbonyl; C₁₋₆alkyloxycarbonyl; aryl; di(aryl)methyl; or C₁₋₆ alkyl substituted withhydroxy, C₁₋₆ alkyloxy, carboxyl, C₁₋₆ alkylcarbonyloxy, C₁₋₆alkyloxycarbonyl or aryl; R³, R⁴, R⁵, R⁶, R⁹, R¹⁰, R¹¹ and R¹² eachindependently are hydrogen, halo, cyano, hydroxy, trifluoromethyl,trifluoromethoxy, carboxyl, nitro, amino, mono- or di(C₁₋₆ alkyl )amino, C₁₋₆ alkylcarbonylamino, aminosulfonyl, mono- or di(C₁₋₆ alkyl)aminosulfonyl, C₁₋₆ alkyl, C₁₋₆ alkyloxy, C₁₋₆ alkylcarbonyl or C₁₋₆alkyloxycarbonyl; R⁷ and R⁸ each independently are hydrogen, hydroxy,C₁₋₆ alkyl, or C₁₋₆ alkyloxy; or R⁷ and R⁸ taken together may formmethylene; mono- or di(cyano)methylene; or a bivalent radical of theformula --(CH₂)₂ --, --(CH₂)₃ --, --(CH₂)₄ --, --(CH₂)₅ --, --O--(CH₂)₂--O-- or --O--(CH₂)₃ --O--; or R⁷ and R⁸ taken together with the carbonto which they are attached may form a carbonyl; R¹³ is hydrogen, C₁₋₆alkyl or trifluoromethyl; R¹⁴ is hydrogen, C₁₋₆ alkyl, cyano ortrifluoromethyl; and n is a number having a value of from 0 to 6,inclusive; wherein in the foregoing aryl is phenyl or phenyl substitutedwith 1, 2 or 3 substituents selected from the group consisting of halo,hydroxy, C₁₋₆ alkyl and trifluoromethyl.
 2. A compound according toclaim 1, wherein R⁷ and R⁸ each independently are hydrogen or methyl, orwherein R⁷ and R⁸ are taken together to form methylene.
 3. A compoundaccording to claim 2, wherein R¹³ is hydrogen or methyl.
 4. A compoundaccording to claim 3, wherein R¹⁴ is hydrogen, cyano or methyl.
 5. Acompound according to claim 4, wherein the aromatic substituents R⁴, R⁵and R¹¹ each independently are selected from hydrogen, fluoro, chloro,bromo, methyl or trifluoromethyl; the remaining aromatic substituentsbeing hydrogen.
 6. A compound according to claim 5, wherein n is 1 or 2,R¹ is hydrogen or methyl and R² is methyl.
 7. A compound according toclaim 1, wherein the compound iscis-2,3,3a,8-tetrahydro-N,N-dimethyldibenz[c,f]isoxazolo[2,3-a]azepine-2-methanamine;orcis-2,3,3a,8-tetrahydro-N-methyldibenz[c,f]isoxazolo[2,3-a]azepine-2-methanamine,the stereochemically isomeric forms thereof and their pharmaceuticallyacceptable acid addition salts, and also their N-oxide forms.
 8. Acompound of formula ##STR18## wherein R³ to R¹³ are defined as in claim1, an acid or base addition salt thereof or a stereochemically isomericform thereof.
 9. A composition comprising a pharmaceutically acceptablecarrier and, as active ingredient, a therapeutically effective amount ofa compound as defined in claim
 1. 10. A composition comprising apharmaceutically acceptable carrier and, as active ingredient, atherapeutically effective amount of a compound as defined in claim 2.11. A composition comprising a pharmaceutically acceptable carrier and,as active ingredient, a therapeutically effective amount of a compoundas defined in claim
 3. 12. A composition comprising a pharmaceuticallyacceptable carrier and, as active ingredient, a therapeuticallyeffective amount of a compound as defined in claim
 4. 13. A compositioncomprising a pharmaceutically acceptable carrier and, as activeingredient, a therapeutically effective amount of a compound as definedin claim
 5. 14. A composition comprising a pharmaceutically acceptablecarrier and, as active ingredient, a therapeutically effective amount ofa compound as defined in claim
 6. 15. A composition comprising apharmaceutically acceptable carrier and, as active ingredient, atherapeutically effective amount of a compound as defined in claim 7.16. A method for the treatment of central nervous system disordersselected from the group consisting of psychosis, schizophrenia,migraine, anxiety, depression, and addiction to drugs of abuse, whichcomprises administering a therapeutically effective amount of a compoundas defined in claim
 1. 17. A method for the treatment of central nervoussystem disorders selected from the group consisting of psychosis,schizophrenia, migraine, anxiety, depression, and addiction to drugs ofabuse, which comprises administering a therapeutically effective amountof a compound as defined in claim
 2. 18. A method for the treatment ofcentral nervous system disorders selected from the group consisting ofpsychosis, schizophrenia, migraine, anxiety, depression, and addictionto drugs of abuse, which comprises administering a therapeuticallyeffective amount of a compound as defined in claim
 3. 19. A method forthe treatment of central nervous system disorders selected from thegroup consisting of psychosis, schizophrenia, migraine, anxiety,depression, and addiction to drugs of abuse, which comprisesadministering a therapeutically effective amount of a compound asdefined in claim
 4. 20. A method for the treatment of central nervoussystem disorders selected from the group consisting of psychosis,schizophrenia, migraine, anxiety, depression, and addiction to drugs ofabuse, which comprises administering a therapeutically effective amountof a compound as defined in claim
 5. 21. A method for the treatment ofcentral nervous system disorders selected from the group consisting ofpsychosis, schizophrenia, migraine, anxiety, depression, and addictionto drugs of abuse, which comprises administering a therapeuticallyeffective amount of a compound as defined in claim
 6. 22. A method forthe treatment of central nervous system disorders selected from thegroup consisting of psychosis, schizophrenia, migraine, anxiety,depression, and addiction to drugs of abuse, which comprisesadministering a therapeutically effective amount of a compound asdefined in claim 7.